SHOX Whole Gene Duplications Are Overrepresented in SHOX Haploinsufficiency Phenotype Cohorts.

Transcription of SHOX is dependent upon the interaction of the gene with a complex array of flanking regulatory elements. Duplications that contain flanking regulatory elements but not the SHOX gene have been reported in individuals with SHOX haploinsufficiency syndromes, suggesting that alterations to the physical organisation or genomic architecture may affect SHOX transcription. Individuals with tall stature and an additional X or Y chromosome have an extra copy of both the SHOX gene and the entire SHOX regulatory region, so all three copies of SHOX can be expressed fully. However, for a duplication of the SHOX gene that does not include all of the flanking regulatory elements, the potential effect on SHOX expression is difficult to predict. We present nine unpublished individuals with a SHOX whole gene duplication in whom the duplication contains variable amounts of the SHOX regulatory region, and we review 29 similar cases from the literature where phenotypic data were clearly stated. While tall stature was present in a proportion of these cases, we present evidence that SHOX whole gene duplications can also result in a phenotype more typically associated with SHOX haploinsufficiency and are significantly overrepresented in Leri-Weill dyschondrosteosis and idiopathic short stature probands compared to population controls. Although similar-looking duplications do not always produce a consistent phenotype, there may be potential genotype-phenotype correlations regarding the duplication size, regulatory element content, and the breakpoint proximity to the SHOX gene. Although ClinGen does not currently consider SHOX whole gene duplications to be clinically significant, the ClinGen triplosensitivity score does not take into account the context of the duplication, and more is now known about SHOX duplications and the role of flanking elements in SHOX regulation. The evidence presented here suggests that these duplications should not be discounted without considering the extent of the duplication and the patient phenotype, and should be included in diagnostic laboratory reports as variants of uncertain significance. Given the uncertain pathogenicity of these duplications, any reports should encourage the exclusion of all other causes of short stature where possible.

Impact of Automated Information Sharing on Health Care Delivery to Youths in Foster Care.

Children in foster care have higher health care costs and poor care coordination, often due to inconsistent information exchanged between health care and child welfare systems. This study implemented secure automated information sharing and detected improvements in time spent gathering information, health care services delivered, and billing practices at participating health care systems.

Development and Preliminary Validation of a Multidimensional Psychosocial Assessment Strategy for Young Adults With Cancer.

OBJECTIVE: Regular psychosocial assessment is a best-practice guideline for young adult oncology care, but multipurpose, multidimensional, developmentally appropriate patient-reported outcome measurement strategies for young adults with cancer are lacking. This study reported on the development and preliminary validation of the Young Adult Psychosocial Assessment Strategy (YA-PAS), a tool designed to meet this clinical need. METHODS: The YA-PAS was developed based on the literature and clinician feedback. 20 young adults with cancer participated in cognitive interviews to provide feedback on complexity, readability, and applicability to inform measure refinement. Following refinements, 100 young adults with a history of cancer participated in an observational study including a preliminary evaluation of YA-PAS factor structure, internal consistency, test-retest reliability, construct and criterion validity, feasibility, and acceptability. RESULTS: Cognitive interviews and psychometric evaluation informed modifications and resulted in a measure with 9 domains (anxiety, depression, cognitive functioning, post-traumatic stress, family stressors, support, social isolation, self-efficacy for symptom management, and self-efficacy for medication management) and nonscoring items assessing substance use, life stressors, resources, educational/vocational status, and relationship status. 8 of 9 domains demonstrated acceptable internal consistency (Cronbach's α ≥ 0.70), substantial (r = 0.61-0.80) or almost perfect (r > 0.80) test-retest reliability, and evidence of domain and cut-point validity. 89% of participants were able to complete the YA-PAS within 20 min and 87% were satisfied with the measure. CONCLUSIONS: The YA-PAS demonstrated promising psychometric properties, feasibility, and acceptability. Clinical implications and research recommendations are discussed.

Opportunities for Enhanced Transition of Care Preparation for Adolescents and Emerging Adults With Type 1 Diabetes: Use of the READDY Transition Tool.

There is an ongoing need to determine best practices for effective transition from pediatric to adult care for adolescents and emerging adults (EAs) with type 1 diabetes given the potential for poor health outcomes post-transfer. This study evaluated self-reported confidence ratings as measured by the Readiness of Emerging Adults with Diabetes Diagnosed in Youth (READDY) tool among adolescents and EAs with type 1 diabetes and the association of the confidence ratings with clinical and demographic characteristics, as well as provider documentation of relevant anticipatory guidance topics. The READDY is a diabetes-specific tool used to collect patient-reported confidence in transition preparation topics to target educational interventions. These interventions are divided into four domains: Diabetes Knowledge, Health System Navigation, Insulin Self-Management, and Health Behaviors. A retrospective chart review was conducted of patients 15-24 years of age with type 1 diabetes who completed the READDY survey between January 2017 and January 2018 at a single center. Overall patient-reported confidence levels were high. However, adolescents and EAs endorsed their lowest levels of confidence on items assessing knowledge of alcohol, tobacco, sexual health, and the impact of diabetes on pregnancy (females only), with the percentages of low scores of 20.7, 25.9, 35.9, and 42.9%, respectively. Documentation of provider counseling about screening and prevention of diabetes comorbidities, alcohol use, and tobacco use was associated with scores in the higher range for the corresponding item in the READDY survey. These findings highlight an opportunity to create interventions related to developmentally important topics for adolescents and EAs with type 1 diabetes to enhance successful transition preparation.

Enrollment and outcomes of home visiting for mothers with and without a history of out-of-home care.

Women previously in out-of-home care (i.e., foster care) experience poorer health and psychosocial outcomes compared to peers, including higher pregnancy rates and child protective services involvement. Home visiting programs could mitigate risks. Studies examining home visiting enrollment for women with a history of out-of-home care are needed. Women previously in out-of-home care based on child welfare administrative data between 2012 and 2017 (n = 1375) were compared to a demographically matched sample (n = 1375) never in out-of-home care. Vital records data identified live births in the two groups. For those who had given live birth (n = 372), linked administrative data were used to determine and compare rates of referral and enrollment into home visiting, and two indicators of engagement: number of days enrolled, and number of visits received. Women previously in out-of-home care were referred for home visiting more often than their peers. There were no differences in rates of enrollment. Women previously in out-of-home care remained enrolled for shorter durations and completed fewer home visits than peers. Findings suggest barriers to home visiting enrollment and retention in home visiting programs for women previously in out-of-home care. Studies with larger samples and more complete assessments of outcomes are warranted.

Introducción: Las mujeres que previamente han estado bajo cuidado fuera de cada (v.g. hogares de cuidado adoptivo temporal) experimentan una más débil salud y resultados sicosociales en comparación con las compañeras, incluyendo tasas más altas de embarazos y participación en servicios de protección a la niñez. Los programas de visitas a casa pudieran mitigar los riesgos. Se necesitan estudios que examinen la entrada en programas de visitas a casa de mujeres con un historial de cuidado fuera de casa. Métodos: Se comparó la información administrativa entre 2012 y 2017 de mujeres (n = 1375) que previamente estuvieron en cuidados fuera de casa basados en la beneficencia infantil con un grupo muestra demográficamente emparejado (n = 1375) que nunca habían estado bajo cuidado fuera de casa. Los datos vitales registrados identificaron nacimientos vivos en los dos grupos. Para quienes habían tenido un parto y nacimiento vivo (n = 372), se usó la información administrativa conectada para determinar y comparar las tasas de referencia y entrada en programas de visitas a casa, y dos indicadores de participación: el número de días en que estuvieron matriculadas y el número de visitas recibidas. Resultados: A las mujeres previamente bajo cuidado fuera de casa se les refirió a los programas de visita a casa más a menudo que a sus compañeras. No se dieron diferencias en las tasas de matrícula. Las mujeres previamente bajo cuidado fuera de casa permanecieron matriculadas por duraciones más cortas y completaron menos visitas a casa que sus compañeras. Conclusiones: Los resultados identifican barreras a la matrícula y retención en programas de visitas a casa para mujeres previamente bajo cuidado fuera de casa. Se justifican los estudios con grupos muestras más grandes y evaluaciones más completas de los resultados.

Les femmes ayant été placées en famille ou foyer d'accueil font l'expérience d'une plus mauvaise santé et de résultats psychologiques moins bons que les autres femmes, y compris des taux de grossesse plus élevés et l'intervention de services de protection de l'enfance. Les programmes de visite à domicile peuvent mitiger les risques. Les études examinant l'inscription aux visites à domicile pour les femmes ayant un passé de placement en famille ou en foyer sont nécessaires. Méthodes: des femmes ayant vécu un placement en famille ou en foyer selon les données administratives de la protection de l'enfance entre 2012 et 2017 (n = 1375) ont été comparées à un échantillon assorti démographiquement (n = 1375) de femmes n'ayant jamais été placées en famille ou foyer d'accueil. Nous avons identifié des naissances vivantes chez les deux groupes. Pour celles ayant donné naissance (naissance vivante) (n = 372) les données administratives liées ont été utilisées afin de déterminer et de comparer les taux d'orientation et d'inscription aux visites à domicile, et deux indicateurs d'engagement: le nombre de jours inscrites et le nombre de visites reçues. Résultats: les femmes ayant été placées dans des familles ou des foyers d'accueil étaient dirigées vers les visites à domicile plus souvent que leurs pairs. Il n'y avait aucune différence dans les taux d'inscription. Les femmes ayant été en familles ou foyers d'accueil sont restées inscrites pendant des durées plus courtes et ont eu moins de visites à domiciles que leurs pairs. Conclusions: les résultats suggèrent qu'il existe des barrières à l'inscription aux visites à domicile et à la rétention dans les programmes de visites à domicile pour les femmes ayant été placées en famille ou en foyer. Des études avec des échantillons plus grands et des évaluations plus compètes sont justifiées.

Developmental Service Referrals and Utilization Among Young Children in Protective Custody.

Children in foster care are at high risk for developmental delay. In this retrospective cohort study of young children presenting to a foster care clinic, 77% were not receiving developmental services and 75% failed developmental screening. Of those potentially eligible, 60% were not referred for developmental services.

Young Adults With Type 1 Diabetes Preparing to Transition to Adult Care: Psychosocial Functioning and Associations With Self-Management and Health Outcomes.

BACKGROUND | Young adulthood is a vulnerable developmental period associated with increased risk for suboptimal health outcomes in youth with type 1 diabetes. Psychosocial factors have been associated with self-management and glycemic control in younger populations, but the extent to which these associations exist among young adults is poorly understood. This study aimed to examine the psychosocial functioning of young adults with type 1 diabetes and associated clinical outcomes. METHODS | Participants included young adults (n = 44) between the ages of 18 and 23 years in a pediatric setting who were preparing to transition to adult care. All participants completed self-report measures of psychosocial functioning at baseline as part of this longitudinal observational study. Outcome data included glycemic control, frequency of blood glucose monitoring, and self-management ratings at baseline and 1-year follow-up. RESULTS | Young adults with type 1 diabetes reported higher levels of depressive symptoms, lower self-efficacy, and more risk behaviors compared with previously published scores for adolescents. Young adults also reported greater resilience and transition readiness than their younger counterparts. Psychosocial variables were differentially related to glycemic control and frequency of blood glucose monitoring both cross-sectionally and longitudinally. CONCLUSION | This study provides key information about the psychosocial functioning of young adults with type 1 diabetes. It identifies relevant psychosocial factors that are associated with meaningful health outcomes during the transition preparation period. These findings may inform the development of clinical programs aimed at promoting transition preparation and health outcomes in young adults with type 1 diabetes.

Strategies for Assessing and Modeling Depressive Symptoms in Longitudinal Studies of Adolescents.

Studying age-related change in psychosocial behavior is difficult because manifestation differs with development. While the use of age-appropriate measurement instruments addresses developmental differences, changes in measurement also challenge researchers' ability to study developmental trajectories. Leveraging 8-occasion data from 262 girls (baseline ages 11 and 17 years) participating in a cross-sequential study spanning childhood to adulthood, this paper (1) highlights the needs of developmental researchers seeking to measure change across large swaths of development, (2) forwards an initial formula to convert Beck Depression Inventory-II scores into Children's Depression Inventory scores and facilitate longitudinal analysis and understanding of how depression develops across adolescence, and (3) suggests collection and analysis of new data that would better facilitate researcher's linking of child-, adolescent-, and adult-oriented measurement instruments.

Is Sexual Abuse a Unique Predictor of Sexual Risk Behaviors, Pregnancy, and Motherhood in Adolescence?

This study tested sexual abuse as a unique predictor of subsequent adolescent sexual behaviors, pregnancy, and motherhood when in company with other types of maltreatment (physical abuse, neglect) and alternative behavioral, family, and contextual risk factors in a prospective, longitudinal study of maltreated (n = 275) and comparison (n = 239) nulliparous females aged 14-19 years old assessed annually through 19 years old. Hierarchical regression was used to disentangle risk factors that account for the associations of maltreatment type on risky sexual behaviors at 19 years old, adolescent pregnancy, and adolescent motherhood. Findings indicate that sexual and physical abuse remain significant predictors of risky sexual behaviors, and that sexual abuse remains a significant predictor of adolescent motherhood when alternative explanatory variables are controlled.

Relationship between cancer-related traumatic stress and family milestone achievement in adolescent and young adult survivors of childhood cancer.

Late physical and emotional effects of cancer treatment pose a burden for adolescent and young adult survivors of childhood cancer, including family milestone achievement. This brief report examined links between ongoing cancer-related post-traumatic stress symptoms (CR-PTSS) and family milestone achievement. Survivors (n = 51; Mage  = 24.73, SD = 8.20) completed CR-PTSS and family formation questionnaires. Descriptive statistics, univariate parameter-constraints, and correlation analyses examined relations among study variables. Ongoing intrusive thoughts and hyperarousal were negatively linked to family identity development and family achievement. Findings from the present study provide support that ongoing CR-PTSS may be a barrier to family formation.

Examining the Validity of Self-reported Primary and Secondary Exposure to Cigarette Smoke in Adolescent Girls: The Utility of Salivary Cotinine as a Biomarker.

BACKGROUND: Studies of cigarette use and exposure often rely on either self-report or cotinine assay. In adolescence it is not clear how well assays and self-report correspond, or what effect estrogen exposure has on cotinine. OBJECTIVES: This study sought to identify optimal cut-points for salivary cotinine thresholds for girls with primary, secondary, and no smoke exposure, and whether menarche and hormone contraceptive use are important for interpreting salivary cotinine. METHODS: This longitudinal prospective study recruited 262 healthy adolescent girls who participated in three annual interviews across 24 months. Salivary cotinine assays and self-report of primary and secondary smoke exposure, menarcheal status, and hormone contraceptive use were collected. RESULTS: No adolescents reported primary smoke exposure without secondary exposure. Optimal cut-points for distinguishing primary smoke exposure from secondary-only and no smoke exposure were 1.05 and 3.01 ng/ml, respectively based on receiver operator curves (ROC); no reliable cut-point for secondary-only versus no smoke exposure was identified. The ideal salivary cotinine cut-point to distinguish primary smoke exposure varied by hormone contraceptive use and was 2.14 ng/ml for those using progesterone contraceptives, higher than that of girls using estrogen contraceptives and those not using hormone contraceptives. CONCLUSIONS: This study is the first to examine variance in salivary cotinine cut-points based on hormone exposure for adolescent girls, with findings indicating that hormone contraceptive use in particular may be a key consideration when identifying adolescent smoking. The use of previously recommended salivary cotinine cut-points of 3.85 ng/ml or higher may overestimate nonsmokers.

Developing a Health Care System for Children in Foster Care.

In 2012, the Comprehensive Health Evaluations for Cincinnati's Kids (CHECK) Center was launched at Cincinnati Children's Hospital Medical Center to provide health care for over 1,000 children placed into foster care each year in the Cincinnati community. This consultation model clinical program was developed because children in foster care have been difficult to manage in the traditional health care setting due to unmet health needs, missing medical records, cumbersome state mandates, and transient and impoverished social settings. This case study describes the history and creation of the CHECK Center, demonstrating the development of a successful foster care health delivery system that is inclusive of all community partners, tailored for the needs and resources of the community, and able to adapt and respond to new information and changing systems.

Children in nonparental care: health and social risks.

Approximately 2.3 million children in the United States live separately from both parents; 70-90% of those children live with a relative. Compared with children living with one or both parents, children in nonparental care are in poorer health, are at heightened risk for experiencing disruptions and instability in caregiving, and are vulnerable to other social antecedents of child health (e.g., neglect, poverty, maltreatment). Given the significant impact of adversity in childhood on health across the lifespan, which is increased among children in nonparental care, it is informative to consider the health risks of children living in nonparental care specifically. Research examining the contributions of poverty, instability, child maltreatment, and living in nonparental care, including meta-analyses of existing studies, are warranted. Longitudinal studies describing pathways into and out of nonparental care and the course of health throughout those experiences are also needed. Despite these identified gaps, there is sufficient evidence to indicate that attention to household structure is not only relevant but also essential for the clinical care of children and may aid in identifying youth at risk for developing poor health across the lifespan.

Morningness-Eveningness and Physical Activity in Adolescent Girls: Menarche as a Transition Point.

This study identified trajectories of morningness-eveningness (M-E) and physical activity when chronological (i.e., time since birth) versus gynecological (i.e., time since menarche) age is used to indicate maturation. Piecewise models were fit for girls (N = 262, ages 11-19) using chronological or gynecological age as the time metric. Girls stayed up later (i.e., eveningness) as they approach menarche. After menarche no change in M-E was observed. In contrast, no change in M-E was detected with chronological age. No change in physical activity was observed before menarche, and physical activity declined after menarche. With chronological age, physical activity declined as girls got older. Gynecological age may be more appropriate than chronological age as a metric for understanding changes in M-E and physical activity.

Pallister-Killian syndrome: a study of 22 British patients.

BACKGROUND: Pallister-Killian syndrome is a rare, sporadic condition caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). The main features are intellectual disability, seizures, dysmorphic features and a variety of congenital malformations. Most available information comes from individual case reports. We report the results of a British study into Pallister-Killian syndrome, which is the first to provide comprehensive data on a population-based sample. METHOD: A detailed phenotypical study was carried out in Great Britain. All individuals with Pallister-Killian syndrome were eligible to participate. Each participant underwent a structured history, developmental assessment and clinical examination. Buccal mucosal samples were analysed by interphase fluorescence in situ hybridization (FISH) and blood samples by array comparative genomic hybridization (CGH). Genotype-phenotype correlations were sought in these tissues and existing skin biopsy reports. RESULTS: Twenty-two patients with Pallister-Killian syndrome, ranging from 4 months to 31 years were recruited and comprehensive data on each obtained. The birth incidence was 5.1 per million live births. Array CGH only suggested the diagnosis in 15.8% but buccal FISH could have made the diagnosis in 75.0%. There was no genotype-phenotype correlation in any of the tissues studied. This study shows that the high birth weights and profound intellectual disability classically described in Pallister-Killian syndrome are not universal. Mild or moderate intellectual disability was present in 27.6% of this cohort and all birth weights were within 2.67SD of the mean. New features which have not previously been recognised as part of Pallister-Killian syndrome include anhydrosis/hypohydrosis and episodic hyperventilation, suggesting involvement of the autonomic system.

Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance.

The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.

Characterizing the longitudinal relations between depressive and menstrual symptoms in adolescent girls.

OBJECTIVE: This study examined the association between depressive and menstrual symptoms in adolescent girls in a 3-year longitudinal study. It was hypothesized that menstrual symptoms would increase in early adolescence and decrease in later adolescence, that girls with greater depressive symptoms would report greater menstrual symptoms, and that effects would persist after adjusting for general somatic complaints. METHODS: A community sample of girls (n = 262) enrolled in an observational study by age cohort (11, 13, 15, 17 years) completed three annual visits. At each time point, girls completed the Menstrual Symptom Questionnaire, Children's Depression Inventory, and the Youth Self Report to assess general somatic complaints. RESULTS: Menstrual symptoms increased significantly across adolescence (p = .006) and began to plateau in later adolescence (p = .020). Depressive symptoms at study entry were significantly associated with menstrual symptoms (p < .001). When general somatic complaints were included in the models, the effect of depressive symptoms on menstrual symptoms remained significant for the sum score (p = .015) and the menstrual somatic symptoms subscale (p = .001). After adjusting for somatic complaints, initial report of depressive symptoms predicted change in menstrual symptoms only for girls with the lowest menstrual symptoms sum score (p = .025). Initial report of somatic complaints predicted change in menstrual symptoms (p = .020). CONCLUSIONS: Girls with higher depressive symptoms and higher somatic complaints are at greater risk for experiencing menstrual symptoms and increasing symptoms across adolescence, with a heightened vulnerability for girls with lower baseline menstrual symptoms.

Salivary cytokines in healthy adolescent girls: Intercorrelations, stability, and associations with serum cytokines, age, and pubertal stage.

Theoretically, the measurement of cytokines in saliva may have utility for studies of brain, behavior, and immunity in youth. Cytokines in saliva and serum were analyzed across three annual assessments in healthy adolescent girls (N = 114, 11-17 years at enrollment). Samples were assayed for GM-CSF, IFNγ, IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNFα, adiponectin, and cotinine. Results revealed: (1) cytokine levels, except IFNγ and IL-10, were detectable in saliva, and salivary levels, except IL-8 and IL-1ß, were lower than serum levels; (2) salivary cytokine levels were lower in older girls and positively associated with adiponectin; (3) compared to serum levels, the correlations between salivary cytokines were higher, but salivary cytokines were less stable across years; and (4) except for IL-1ß, there were no significant serum-saliva associations. Variation in basal salivary cytokine levels in healthy adolescent girls reflect compartmentalized activity of the oral mucosal immune system, rather than systemic cytokine activity.